Antimicrobial peptides have diverse functions, serving not only to directly attack pathogens, but also as chemotactic agents and as an alarm system that activates host immune cells. Human beta defensin-3 (hBD3) is an important antimicrobial peptide produced at mucosal surfaces and which can cause activation of monocytes and other antigen-presenting cells. New preliminary data provide evidence that hBD3 is found in platelets and can activate platelets through molecular pathways that are currently undefined. Platelets patrol the circulatory system for vascular injury and are intimately involved in blood clotting processes. Moreover, these cells provide rapid responses to injury and when activated, release stored contents that have potent effects on the immune system. The proposed studies will investigate platelet activation by hBD3, including the molecular pathways involved (Aim 1), the expression of hBD3 in platelet granules and microparticles (Aim 2) and the potential crosstalk between platelets and monocytes that may be orchestrated by this antimicrobial peptide (Aim 3). The expression and activity of hBD3 that will be defined in platelets by these proposed studies may uncover a new paradigm at the intersection of platelets and host immunity.